Paul Nyirjesy

Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies

Abstract Objective: To characterize genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) using pooled data from Phase 3 studies. Research design and methods: Genital mycotic infections with canagliflozin 100 and 300u2009mg were evaluated in Population 1 (Nu2009=u20092313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8), including patients from four placebo-controlled studies, and Population 2 (Nu2009=u20099439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4), including patients from eight placebo/active-controlled studies (including older patients and those with renal impairment or high cardiovascular disease risk). Clinical trial registration: ClinicalTrials.gov identifier: NCT01081834. ClinicalTrials.gov identifier: NCT01106625. ClinicalTrials.gov identifier: NCT01106677. ClinicalTrials.gov identifier: NCT01106690. ClinicalTrials.gov identifier: NCT01032629. ClinicalTrials.gov identifier: NCT01064414. ClinicalTrials.gov identifier: NCT01106651. ClinicalTrials.gov identifier: NCT00968812. Main outcome measures: Adverse events suggestive of genital mycotic infections were recorded, with additional information collected using supplemental electronic case report forms. Results: In Population 1, genital mycotic infection incidence was higher with canagliflozin 100 and 300u2009mg than placebo (95% confidence intervals excluded zero) in females (10.4%, 11.4%, 3.2%) and males (4.2%, 3.7%, 0.6%). These were generally mild to moderate in intensity, none were serious, and few led to discontinuation. Most events with canagliflozin were treated with antifungal therapies, and median symptom duration following treatment initiation was similar across groups; few patients had >1 event (females, 2.3%; males, 0.9%). Findings with canagliflozin 100 and 300u2009mg versus control were similar in Population 2 (females: 14.7%, 13.9%, 3.1%; males: 7.3%, 9.3%, 1.6%); a low proportion of males underwent circumcision across groups. Most events with canagliflozin occurred within the first 4 months in females and first year in males; no consistent evidence of dose dependence was observed. Key limitations included lack of laboratory confirmation for most events and variable treatment methods. Conclusions: Genital mycotic infection incidences were higher with canagliflozin than control in patients with T2DM; events were generally mild to moderate in intensity and responded to standard treatments.

Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor

Abstract Background/objective: Women with type 2 diabetes mellitus (T2DM) are at increased risk for vaginal Candida colonization, perhaps because of glucosuria. Sodium glucose co-transporter 2 (SGLT2) inhibitors, in development for the treatment of T2DM, improve glycemic control by increasing urinary glucose excretion. Vaginal Candida colonization and symptomatic vulvovaginal adverse events (VVAE) were assessed in females with T2DM treated with canagliflozin, a SGLT2 inhibitor. Methods: In a double-blind study, subjects with T2DM and inadequate glycemic control on metformin were randomized to placebo; canagliflozin 50, 100, 200, 300u2009mg daily or 300u2009mg twice daily; or sitagliptin 100u2009mg daily for 12 weeks. Vaginal swabs for Candida culture were collected from 198 female subjects at baseline and week 12, and during the trial if symptoms consistent with vulvovaginal candidiasis occurred. Results: At baseline, 23/198 (12%) females had vaginal cultures positive for Candida (C. glabrata: 14; C. albicans: 5; other: 4), with age ≤55 years associated with increased risk (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.1–10.7). Of those with negative cultures at baseline, 31% of canagliflozin and 14% of placebo/sitagliptin subjects converted to positive at week 12 (OR, 2.8; 95% CI, 1.0–7.3 for canagliflozin vs. placebo/sitagliptin). Two placebo/sitagliptin (3%) and 16 canagliflozin subjects (10%) experienced VVAE. Positive vaginal culture for Candida species at baseline was a risk factor for VVAE (OR, 9.1; 95% CI, 2.4–34.0). All 9/9 subjects in the canagliflozin group with a vaginal culture taken at the time of the VVAE were positive for Candida species. Most VVAE were treated with antifungal therapy and resolved without study drug interruption; none led to discontinuation. Study limitations include small population, short duration, and not obtaining cultures in all women with VVAE. Conclusion: Canagliflozin treatment was associated with an increase in vaginal colonization with Candida species and in VVAE in women with T2DM. Trial registration: ClinicalTrials.gov identifier: NCT00642278.

Metronidazole-Resistant Vaginal Trichomoniasis — An Emerging Problem

To the Editor: Trichomonal resistance to metronidazole was reported soon after its introduction and has been reported in many areas in the world. Although a sexually transmitted disease with dire consequences related to human immunodeficiency virus transmission, trichomoniasis is not a reportable infection, and epidemiologic data on its incidence in the United States are not available. Therefore, it is not surprising that accurate figures on metronidazole-resistant trichomoniasis are almost nonexistent. Nevertheless, clinically important resistance is considered rare, with estimates of high-level resistance to metronidazole occurring in only 1 in 2000 to 3000 cases.1 In clinics specializing in chronic vaginitis that .xa0.xa0.

Vulvovaginal Candidiasis and Bacterial Vaginosis

Vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV) are frequently encountered in clinical practice. Recent advances have furthered understanding of pathophysiology. Proper diagnosis, based on appropriate office and, in complicated cases, laboratory tests is the key to rational selection of therapy. For women who have routine uncomplicated episodes of VVC or BV, a variety of effective treatment options exists. Recurrent disease remains a challenge for these conditions but can often be managed successfully.

Causes of Chronic Vaginitis Analysis of a Prospective Database of Affected Women

OBJECTIVE: To compare women with different chronic vaginal symptoms with a wide variety of sociodemographic, health, behavioral, and psychosocial characteristics. METHODS: Serially recruited subjects answered a questionnaire that asks about demographic information and symptoms and measures depression and stress scores. Patients underwent a standardized history, physical examination, and laboratory examination. Patients with recurrent vulvovaginal candidiasis, vulvar vestibulitis syndrome, desquamative inflammatory vaginitis, physiologic leukorrhea, and other diagnoses were compared with one another. Chi-square tests and one-way analysis of variance with Tukey honestly significant difference (HSD) post hoc analyses were used for categorical and continuous data analysis. RESULTS: Two hundred patients were enrolled in this study. The most common diagnoses were contact dermatitis (21%), recurrent vulvovaginal candidiasis (20.5%), atrophic vaginitis (14.5%), and vulvar vestibulitis syndrome (12.5%); 18% of women had 2 or more diagnoses. In the overall study sample, the mean age was 38.4 years, 78% were white, and 55% were college educated. Sixty-two percent had symptoms for over a year. Desquamative inflammatory vaginitis patients were older and less likely to be menstruating. Those with vulvar vestibulitis syndrome had more frequent complaints of dyspareunia. Recurrent vulvovaginal candidiasis patients felt that their symptoms had the greatest negative impact on work and social life. There were high rates of psychiatric disorder (43.5%), atopic disease (42.5%), and pain syndrome (56%) in all groups. CONCLUSION: Women with chronic vaginal symptoms have a variety of diagnoses, most of them noninfectious. LEVEL OF EVIDENCE: II-3

Genital Mycotic Infections in Patients With Diabetes

Abstract Patients with diabetes, especially those with poorly controlled glycemia, are prone to developing genital mycotic infections—vulvovaginal candidiasis in women and Candida balanitis in men—the latter almost exclusively in uncircumcised men. Candida albicans is the most common pathogen causing balanitis and is also the dominant cause of vulvovaginal candidiasis in women with diabetes, although Candida glabrata is a prominent pathogen in women with type 2 diabetes mellitus. Candida glabrata is less virulent but also less susceptible to conventional antifungal treatment. High blood glucose levels promote yeast attachment and growth, and also interfere with immune responses in the host. In uncircumcised men, the moist, warm space underneath the foreskin is thought to promote yeast growth, especially when hygiene is poor. Several other risk factors have been identified that predispose to genital mycotic infections, including antibiotic use, corticosteroid use, immunosuppression, atopy, and, in women only, genetics, pregnancy, estrogen/oral contraceptive use, and select sexual behaviors (eg, orogenital sex). In patients with hyperglycemia, risk is increased for not only incident infection but also for recurrence, underscoring the key role of establishing and maintaining euglycemia in the management of genital mycotic infections in patients with diabetes. In addition to blood glucose control, first-line treatment involves either an antifungal cream/ointment (or suppository for women only) that is applied intravaginally by women and directly to the affected area(s) by men, or oral treatment, which infrequently causes systemic side effects. Antifungal treatment should also be offered to sexual partners of patients with diabetes with a genital mycotic infection if the partner is similarly infected. Given high efficacy rates, follow-up test-of-cure after the completion of treatment is generally unnecessary.

Vaginal Candida parapsilosis: Pathogen or bystander?

OBJECTIVEnCandida parapsilosis is an infrequent isolate on vaginal cultures; its role as a vaginal pathogen remains unstudied. This retrospective study of women with positive culture for C. parapsilosis sought to characterize the significance of this finding and its response to antifungal therapy.nnnMETHODSnFrom February 2001 to August 2002, we identified all individuals with positive fungal isolates among a population of women with chronic vulvovaginal symptoms. Charts of women with C. parapsilosis cultures were reviewed with regard to patient demographics, clinical presentation and therapeutic response. Mycological cure, defined as a negative fungal culture at the next office visit, and clinical cure, i.e. symptom resolution, were determined for each subject.nnnRESULTSnA total of 582 women had positive vaginal cultures for 635 isolates, of which 54 (8.5%) were C. parapsilosis. The charts of 51 subjects with C. parapsilosis were available for review and follow-up cultures and clinical information were available for 39 (76.5%). Microscopy was positive in 9 (17.6%). Antifungal treatment resulted in mycological cure in 17/19 patients with fluconazole, 7/7 with butoconazole, 6/6 with boric acid, 1/1 with miconazole and occurred spontaneously in 6/7: 24/37 (64.9%) patients with a mycological cure experienced clinical cure.nnnCONCLUSIONSnAlthough C. parapsilosis is often a cause of vaginal symptoms, it seems to respond to a variety of antifungal agents and may even be a transient vaginal colonizer.

Effectiveness of two tinidazole regimens in treatment of bacterial vaginosis: a randomized controlled trial.

OBJECTIVE: To assess the effectiveness at 21–30 days after treatment of tinidazole administered orally at 1 g once daily for 5 days and 2 g once daily for 2 days, compared with placebo, in the treatment of bacterial vaginosis, using rigorous U.S. Food and Drug Administration (FDA)–recommended criteria to define cure. METHODS: A total of 235 women at 10 U.S. centers participated in this prospective, randomized, double-blinded, placebo-controlled trial. Presence or absence of all five following criteria was required to define diagnosis or cure of bacterial vaginosis: 1) clue cells were at least 20% of squamous cells in microscopic examination of vaginal fluid; 2) positive potassium hydroxide whiff test; 3) a homogeneous, thin, white-gray vaginal discharge; 4) vaginal pH greater than 4.5; and 5) Nugent score greater than or equal to 4 on Gram-stained vaginal fluid. Compliance, tolerability, and safety were assessed using patient diaries and interviews at 8–10 days and 21–30 days after treatment. Cochran-Mantel-Haenszel statistical analysis with Bonferroni adjustment was used to compare outcomes. RESULTS: Superior efficacy was demonstrated by tinidazole for the 1 g once daily for 5 days regimen (36.8% cured, P<.001, number needed to treat 3.2) and for the 2 g once daily for 2 days regimen (27.4% cured, P<.001, number needed to treat 4.5), when compared with placebo (5.1% cured) in the primary endpoint analysis. Using more traditional criteria for cure, efficacy was greater. Compliance with study therapy and tolerability were comparable in the three treatment groups. CONCLUSION: Both tinidazole regimens studied provided effective treatment for bacterial vaginosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00229216 LEVEL OF EVIDENCE: I

Role of Mycoplasma and Ureaplasma Species in Female Lower Genital Tract Infections

Genital mycoplasmas are commonly found in the female genital tract. Despite ongoing debate, the evidence that they cause lower genital tract disease in women remains sparse. The data that Mycoplasma genitalium is primarily transmitted sexually are accumulating, but its role as a cause of symptomatic urethritis or cervicitis is open to debate. Although Mycoplasma hominis may be a co-factor in bacterial vaginosis, it has otherwise not been implicated as a cause of lower tract disease. Now that Ureaplasma urealyticum has been divided into U. urealyticum and Ureaplasma parvum, their role in causing urethritis and cervicitis remains even more unclear. To date, no convincing evidence exists that antimicrobial therapy should be directed solely at these organisms when treating women with urethritis, bacterial vaginosis, trichomoniasis, or cervicitis.

The effects of intravaginal clindamycin and metronidazole therapy on vaginal mobiluncus morphotypes in patients with bacterial vaginosis.

Objective: The objective of this study was to compare the effects of treatments for bacterial vaginosis (BV) on vaginal Mobiluncus morphotypes. Study Design: Analyses were performed on Mobiluncus scores from similarly conducted studies evaluating clindamycin vaginal single-dose cream (CVSDC) or metronidazole vaginal gel (MVG) in 55 patients with BV and with Mobiluncus morphotypes at baseline. Results: Both treatment groups demonstrated significant reductions in Mobiluncus score. However, the Mobiluncus score at test-of-cure was lower in the CVSDC than in the MVG group (P = 0.0471). More patients in the CVSDC group than in the MVG group achieved microbiologic (57.5% vs. 26.7%; P = 0.04), clinical (57.5% vs. 26.7%; P = 0.04), and therapeutic cures of BV (45.0% vs. 20.0%; P = 0.09). Conclusion: Clindamycin reduces vaginal Mobiluncus morphotypes to a greater extent than metronidazole in patients with BV; this correlates with a higher BV cure rate.